Leber Congenital Amaurosis (LCA) is the most common form of congenital childhood blindness with an estimated prevalence of approximately 1 in 50,000 newborns, worldwide (Koenekoop et al., 2007; Stone, 2007). It is accompanied by retinal dystrophy. The onset of disease symptoms is as early as the first months or years in life (Leber, T., 1869). Genetically, LCA is a heterogeneous disease, with fifteen genes identified to date in which mutations are causative for LCA (den Hollander et al., 2008; Estrada-Cuzcano et al., 2011). The most frequently mutated LCA gene is CEP290, a gene located on the Q arm of chromosome 12, coding for Centrosomal Protein 290 which has an important role in centrosome and cilia development. Mutations in the CEP290 gene are responsible for about 15% of all LCA cases (Stone, 2007; den Hollander, 2008; den Hollander, 2006; Perrault et al., 2007).
The by far most frequently occurring CEP290 mutation, associated with retinal dystrophy, especially in European countries and in the US, is a change in intron 26 of the CEP290 gene (c.2991+1655A>G) (Stone, 2007; den Hollander et al., 2006; Perrault et al., 2007; Liitink et al., 2010). This mutation creates a cryptic splice donor site in intron 26 which results in the inclusion of an aberrant exon of 128 bp in the mutant CEP290 mRNA, and inserts a premature stop codon (p.C998X) (see FIG. 1). In patients with this mutation, the wild-type transcript that lacks the aberrant exon is still produced, explaining the hypomorphic nature of this mutation (Estrada-Cuzcano et al., 2011).
WO2013/036105 (Stichting Katholieke Universiteit Nijmegen) and WO2012/168435 (Inserm et al.) disclose antisense oligonucleotides for the treatment or delay of LCA, targeting this intronic mutation in CEP290.